Cephem compounds have heretofore been produced by reacting a 7-amino-3-cephem-4-carboxylate derivative or 7-aminocephalosporanic acid derivative, or the like with a carboxylic acid chloride or carboxylic acid in an organic solvent, thereby conducting an amidation. ##STR5##
For example, Japanese Patent Application Laid-Open Nos.125,190/1977, 68,795/1978 and 68,796/1978, which correspond to GB 1576625 and GB 1576626, disclose reaction examples in which 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid is condensed with 7-amino-cepharosporanic acid in the presence of phosphorus oxychloride to produce ceftizoxime.
However, many of 7-amino-3-cephem-4-carboxylate derivatives are hardly soluble in organic solvents and require a large amount of a solvent upon their reactions. Therefore, their use has been extremely disadvantageous from the viewpoint of production cost. Besides, since organic solvents generally have toxicity or flammability, full measures must also be taken for equipment and the like from the viewpoint of work environment. As described above, the conventional production processes making use of an organic solvent have involved problems of bulk material cost and manufacturing facilities.
In addition, since the cephem compounds are used as medicines, products having extremely high purity are required. For this reason, the products are finally purified by column chromatography. Since the cephem compounds themselves are high-polar substances, reverse phase chromatography is in use for purification from the viewpoint of purification efficiency.
When the reaction is carried out using an organic solvent, however, it has been necessary to remove a large amount of the reaction solvent by concentration to replace it by a solvent (polar solvent) for chromatography. There has also been a problem that when the amount of the residual solvent is large due to insufficient concentration, purification efficiency of chromatography is lowered.